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Caloric restriction (Cr) and lithocholic acid (LCa) delay aging by remodeling lipid dynamics in the endoplasmic reticulum (Er), lipid bodies (LB) and peroxisomes. See text for details. the thickness of arrows correlates with the rates of metabolic processes in yeast entered stationary growth phase in nutrient-rich medium. t bars denote inhibition of the process. the metabolites accumulated in bulk quantities are shown in bold. red arrows connote the reduction of a metabolite concentration. ac-Coa, acetyl-Coa; acOH, acetic acid; DaG, diacylglycerols; EtC, electron transport chain; EtOH, ethanol; Fa-Coa, Coa esters of fatty acids; FFa, free fatty acids; taG, triacylglycerols; tCa, tricarboxylic acid cycle.
Source publication
Comment on: Goldberg AA, et al. Aging 2010; 2:393-414.
Citations
... Specifically, during post-diauxic (PD) and the non-proliferative stationary (ST) phases of culturing yeast under CR conditions on 0.2% glucose, LCA also affects the following cellular processes: 1) it increases the concentration of triacylglycerols (TAG), so-called ″neutral″ (uncharged) lipids initially synthesized in the endoplasmic reticulum (ER) and then deposited in lipid droplets (LD) (Supplementary Figure 1); 2) it decreases the concentration of free fatty acids (FFA), which can be used as substrates for TAG synthesis in the ER and can also be formed as the products of TAG lipolysis in LD; FFA can then undergo β-oxidation in peroxisomes (Supplementary Figure 1); 3) it increases the concentrations of the Gpd2, Gpt2, Slc1, Are1 and Dga1 proteins, all of which reside in the ER and are involved in the synthesis of TAG from FFA (Supplementary Figure 1); 4) it decreases the concentrations of the Tgl1, Tgl3, Tgl4 and Tgl5 proteins, all of which exist in LD and catalyze TAG lipolysis that yields FFA (Supplementary Figure 1); 5) it increases the concentrations of Cat2, Crc1, Yat1 and Yat2; these proteins are required for the carnitinedependent transport of acetyl-CoA from peroxisomes www.oncotarget.com (where acetyl-CoA is formed as the final product of the β-oxidation of FFA) to mitochondria (Supplementary Figure 2); 6) it decreases the concentrations of the Cit2, Ctp1 and Dic1 proteins (Cit2 catalyzes a peroxisomal anaplerotic reaction transforming acetyl-CoA into citrate; this reaction is followed by the conversion of citrate into succinate and then by the Ctp1-and Dic1-dependent delivery of citrate and succinate (respectively) to mitochondria) (Supplementary Figure 2); 7) it increases the concentrations of Mpc1 and Mpc3, the two protein components of a mitochondrial pyruvate carrier involved in pyruvate transport to mitochondria during respiratory growth;it does not, however, alter the concentration of the Mpc2 protein component of the mitochondrial pyruvate carrier Mpc1/Mpc2 that assembles and operates during fermentative growth (Supplementary Figure 2); 8) it increases the percentage of cells exhibiting a tubular mitochondrial network and decreases the percentage of cells displaying fragmented mitochondria; 9) it lowers cell susceptibility to an apoptotic mode of regulated cell death (RCD) caused by an exposure to hydrogen peroxide or acetic acid; and 9) it decreases cell susceptibility to liponecrotic RCD triggered by a treatment with FFA [36, 44,50,[52][53][54]73]. It remained unclear how LCA regulates the anabolic and catabolic branches of TAG metabolism in the ER, LD and peroxisomes (Supplementary Figure 1), and how it regulates other cellular processes named in this section. ...
All presently known geroprotective chemical compounds of plant and microbial origin are caloric restriction mimetics because they can mimic the beneficial lifespan-and healthspan-extending effects of caloric restriction diets without the need to limit calorie supply. We have discovered a geroprotective chemical compound of mammalian origin, a bile acid called lithocholic acid, which can delay chronological aging of the budding yeast Saccharomyces cerevisiae under caloric restriction conditions. Here, we investigated mechanisms through which lithocholic acid can delay chronological aging of yeast limited in calorie supply. We provide evidence that lithocholic acid causes a stepwise development and maintenance of an aging-delaying cellular pattern throughout the entire chronological lifespan of yeast cultured under caloric restriction conditions. We show that lithocholic acid stimulates the aging-delaying cellular pattern and preserves such pattern because it specifically modulates the spatiotemporal dynamics of a complex cellular network. We demonstrate that this cellular network integrates certain pathways of lipid and carbohydrate metabolism, some intercompartmental communications, mitochondrial morphology and functionality, and liponecrotic and apoptotic modes of aging-associated cell death. Our findings indicate that lithocholic acid prolongs longevity of chronologically aging yeast because it decreases the risk of aging-associated cell death, thus increasing the chance of elderly cells to survive.
... The ethanol-driven excessive accumulation of unoxidized FFA in yeast peroxisomes (see section 2.10) elicits several negative-feedback loops whose action causes a build-up of FFA and DAG in the ER and lipid droplets (LD) [3,100,101]. This build-up of FFA and DAG accelerates the onset of the liponecrotic mode of RCD, thereby increasing the risk of death and accelerating yeast chronological aging ( Figure 1L) [3,21,[98][99][100]. ...
The concentrations of some key metabolic intermediates play essential roles in regulating longevity of the chronologically aging yeast Saccharomyces cerevisiae. These key metabolites are detected by certain ligand-specific protein sensors that respond to concentration changes of the key metabolites by altering the efficiencies of longevity-defining cellular processes. The concentrations of the key metabolites that affect yeast chronological aging are controlled spatially and temporally. Here, we analyze mechanisms through which the spatiotemporal dynamics of changes in the concentrations of the key metabolites influence yeast chronological lifespan. Our analysis indicates that a distinct set of metabolites can act as second messengers that define the pace of yeast chronological aging. Molecules that can operate both as intermediates of yeast metabolism and as second messengers of yeast chronological aging include NADPH, glycerol, trehalose, hydrogen peroxide, amino acids, sphingolipids, spermidine, hydrogen sulfide, acetic acid, ethanol, free fatty acids and diacylglycerol. We discuss several properties that these second messengers of yeast chronological aging have in common with second messengers of signal transduction. We outline how these second messengers of yeast chronological aging elicit changes in cell functionality and viability in response to changes in the nutrient, energy, stress and proliferation status of the cell.
... Recent studies have revealed that the longevityextending effect of CR in chronologically aging yeast depends on the cellular homeostasis of two classes of lipids, namely triacylglycerols (TAG) and cardiolipins (CL) [2,4,[122][123][124][125][126][127][128][129][130][131][132][133][134][135]. TAG are so-called neutral lipids that in yeast are synthesized in the endoplasmic reticulum and then deposited in lipid droplets to serve as the main storage molecules for maintaining energy homeostasis and supplying free fatty acids [136][137][138][139], whereas CL are signature lipids of the inner mitochondrial membrane implicated in oxidative phosphorylation and several other vital processes confined to mitochondria [140][141][142][143]. ...
A yeast culture grown in a nutrient-rich medium initially containing 2% glucose is not limited in calorie supply. When yeast cells cultured in this medium consume glucose, they undergo cell cycle arrest at a checkpoint in late G1 and differentiate into quiescent and non-quiescent cell populations. Studies of such differentiation have provided insights into mechanisms of yeast chronological aging under conditions of excessive calorie intake. Caloric restriction is an aging-delaying dietary intervention. Here, we assessed how caloric restriction influences the differentiation of chronologically aging yeast cultures into quiescent and non-quiescent cells, and how it affects their properties. We found that caloric restriction extends yeast chronological lifespan via a mechanism linking cellular aging to cell cycle regulation, maintenance of quiescence, entry into a non-quiescent state and survival in this state. Our findings suggest that caloric restriction delays yeast chronological aging by causing specific changes in the following: 1) a checkpoint in G1 for cell cycle arrest and entry into a quiescent state; 2) a growth phase in which high-density quiescent cells are committed to become low-density quiescent cells; 3) the differentiation of low-density quiescent cells into low-density non-quiescent cells; and 4) the conversion of high-density quiescent cells into high-density non-quiescent cells.
... Moreover, it has been shown that 1) a close physical association of peroxisomes with LDs promotes the lipolytic degradation of TAGs within LDs, thus providing bulk quantities of FFAs for beta-oxidation in yeast peroxisomes (130,131,135,136); and 2) lack of peroxisomal Fox1, Fox2 or Fox3 in the fox1Δ, fox2Δ or fox3Δ mutant strain elicits an accumulation of electron-dense arrays of FFAs (which are called ″gnarls″), as well as a deposition of bulk quantities of TAGs, within yeast LDs (130,135,136). Based on all these findings, a mechanism has been proposed for how a CR diet may extend yeast CLS by altering the spatiotemporal dynamics of TAG synthesis in the ER, TAG lipolysis in LDs and beta-oxidation of TAG-derived FFAs in peroxisomes (10,131,161,(171)(172)(173). This mechanism is schematically depicted in Figure 5. ...
... The resulting build-up of FFAs and DAGs in the ER and LDs shortens the CLS of non-CR yeast because these two lipid classes are known to elicit an age-related form of liponecrotic programmed cell death (PCD) (10, 173) ( Figure 5). Because yeast cells grown under CR conditions do not accumulate ethanol (161), they are not susceptible to liponecrotic PCD and thus live longer than non-CR yeast (10,131,161,(171)(172)(173). In the above mechanism, age-related liponecrotic PCD shortens longevity of non-CR yeast. ...
Emergent evidence indicates that certain aspects of lipid synthesis, degradation and interorganellar transport play essential roles in modulating the pace of cellular aging in the budding yeast Saccharomyces cerevisiae. The molecular mechanisms underlying the vital roles of lipid metabolism and transport in defining yeast longevity have begun to emerge. The scope of this review is to critically analyze recent progress in understanding such mechanisms.
... Because unsaturated fatty acids exhibit high susceptibility to age-related oxidative damage, their deposition in the form of TAGs may make LDs the major target of such damage; this would alleviate oxidative damage to macromolecules in other cellular locations [69,70]. In addition, the esterification of unsaturated fatty acids into TAGs may delay yeast chronological aging by attenuating an age-related form of liponecrotic cell death known to be elicited by these fatty acids [67,68,[74][75][76]. ...
The functional state of mitochondria is vital to cellular and organismal aging in eukaryotes across phyla. Studies in the yeast Saccharomyces cerevisiae have provided evidence that age-related changes in some aspects of mitochondrial functionality can create certain molecular signals. These signals can then define the rate of cellular aging by altering unidirectional and bidirectional communications between mitochondria and other organelles. Several aspects of mitochondrial functionality are known to impact the replicative and/or chronological modes of yeast aging. They include mitochondrial electron transport, membrane potential, reactive oxygen species, protein synthesis and proteostasis, as well as mitochondrial synthesis of iron-sulfur clusters, amino acids and NADPH. Our recent findings have revealed that the composition of mitochondrial membrane lipids is one of the key aspects of mitochondrial functionality affecting yeast chronological aging. We demonstrated that exogenously added lithocholic bile acid can delay chronological aging in yeast because it elicits specific changes in mitochondrial membrane lipids. These changes allow mitochondria to operate as signaling platforms that delay yeast chronological aging by orchestrating an institution and maintenance of a distinct cellular pattern. In this review, we discuss molecular and cellular mechanisms underlying the essential role of mitochondrial membrane lipids in yeast chronological aging.
... Specifically, our high-throughput chemical genetic screen for pharmaceuticals that can extend yeast longevity has identified lithocholic acid (LCA), the most hydrophobic bile acid, as one of them [25]. We have uncovered the molecular and cellular mechanisms through which LCA increases the lifespan of chronologically aging yeast [33, 45,55,[238][239][240][241]. It appears that LCA is not only a longevity-extending molecule in yeast but also a potent anti-tumor agent in human cells. ...
A recently conducted chemical genetic screen for pharmaceuticals that can extend longevity of the yeast Saccharomyces cerevisiae has identified lithocholic acid as a potent anti-aging molecule. It was found that this hydrophobic bile acid is also a selective anti-tumor chemical compound; it kills different types of cultured cancer cells if used at concentrations that do not compromise the viability of non-cancerous cells. These studies have revealed that yeast can be successfully used as a model organism for high-throughput screens aimed at the discovery of selectively acting anti-tumor small molecules. Two metabolic traits of rapidly proliferating fermenting yeast, namely aerobic glycolysis and lipogenesis, are known to be similar to those of cancer cells. The mechanisms underlying these key metabolic features of cancer cells and fermenting yeast have been established; such mechanisms are discussed in this review. We also suggest how a yeast-based chemical genetic screen can be used for the high-throughput development of selective anti-tumor pharmaceuticals that kill only cancer cells. This screen consists of searching for chemical compounds capable of increasing the abundance of membrane lipids enriched in unsaturated fatty acids that would therefore be toxic only to rapidly proliferating cells, such as cancer cells and fermenting yeast.
... The other ethanol-dependent mechanism operates in chronologically "old" yeast cells also by slowing down fatty acid oxidation in peroxisomes (Arlia-Ciommo et al., 2014a;Goldberg et al., 2009a,b). The resulting build-up of nonesterified (free) fatty acids in these "old" cells commits them to liponecrosis, an age-related mode of programmed cell death (PCD) (Figure 1(A)) (Beach and Titorenko, 2011;Beach et al., 2012;Goldberg et al., 2009aGoldberg et al., ,b, 2010Leonov and Titorenko, 2013;Richard et al., 2014;Sheibani et al., 2014). Of note, both mechanisms through which ethanol operates as a lifespan-shortening transmissible longevity factor are functional in yeast cells cultured in a medium initially containing 2% glucose and, thus, supplied with excess of calories (Arlia-Ciommo et al., 2014a;Goldberg et al., 2009a,b); under such conditions, yeast cultures accumulate high concentrations of ethanol (Fabrizio et al., 2005;Longo et al., 2012). ...
Cell-autonomous mechanisms underlying cellular and organismal aging in evolutionarily distant eukaryotes have been established; these mechanisms regulate longevity-defining processes within a single eukaryotic cell. Recent findings have provided valuable insight into cell-non-autonomous mechanisms modulating cellular and organismal aging in eukaryotes across phyla; these mechanisms involve a transmission of various longevity factors between different cells, tissues and organisms. Herein, we review such cell-non-autonomous mechanisms of aging in eukaryotes. We discuss the following: (1) how low molecular weight transmissible longevity factors modulate aging and define longevity of cells in yeast populations cultured in liquid media or on solid surfaces, (2) how communications between proteostasis stress networks operating in neurons and non-neuronal somatic tissues define longevity of the nematode Caenorhabditis elegans by modulating the rates of aging in different tissues, and (3) how different bacterial species colonizing the gut lumen of C. elegans define nematode longevity by modulating the rate of organismal aging.
... Moreover, this study and our published data 5,36,38,[68][69][70]72 suggest the following model for how LCA-driven changes in mitochondrial proteome and functionality early and late in life of chronologically aging yeast cause a stepwise development of an 405 anti-aging cellular pattern and its maintenance throughout lifespan (Fig. 7). ...
... A model for how LCA-driven changes in mitochondrial proteome and functionality early and late in life of chronologically aging yeast orchestrate a stepwise development of an anti-aging cellular pattern and its maintenance throughout lifespan. From the data of proteomic analysis (Figs. 1-4) and based on the data of biochemical and cell biological analyses, 36,38,[68][69][70]72,84,85 we inferred an outline of metabolic pathways and processes that were activated (red arrows) or inhibited (green arrows) in cells cultured with exogenous LCA. Arrows next to the names of metabolites, proteins or processes denote those of them whose concentrations or efficiencies were elevated (red arrows) or reduced (green arrows) in cells cultured with exogenous LCA. ...
We have previously revealed that exogenously added lithocholic bile acid (LCA) extends the chronological lifespan of the yeast Saccharomyces cerevisiae, accumulates in mitochondria and alters mitochondrial membrane lipidome. Here, we use quantitative mass spectrometry to show that LCA alters the age-related dynamics of changes in levels of many mitochondrial proteins, as well as numerous proteins in cellular locations outside of mitochondria. These proteins belong to two regulons, each modulated by a different mitochondrial dysfunction; we call them a partial mitochondrial dysfunction regulon and an oxidative stress regulon. We found that proteins constituting these regulons (1) can be divided into several "clusters", each of which denotes a distinct type of partial mitochondrial dysfunction that elicits a different signaling pathway mediated by a discrete set of transcription factors; (2) exhibit three different patterns of the age-related dynamics of changes in their cellular levels; and (3) are encoded by genes whose expression is regulated by the transcription factors Rtg1p/Rtg2p/Rtg3p, Sfp1p, Aft1p, Yap1p, Msn2p/Msn4p, Skn7p and Hog1p, each of which is essential for longevity extension by LCA. Our findings suggest that LCA-driven changes in mitochondrial lipidome alter mitochondrial proteome and functionality, thereby enabling mitochondria to operate as signaling organelles that orchestrate an establishment of an anti-aging transcriptional program for many longevity-defining nuclear genes. Based on these findings, we propose a model for how such LCA-driven changes early and late in life of chronologically aging yeast cause a stepwise development of an anti-aging cellular pattern and its maintenance throughout lifespan.
... A lifespan checkpoint at which several distinct traits of mitochondrial functionality and homeostasis are linked to an age-related "liponecrotic" form of PCD is called checkpoint 7; it exists in ST growth phase [19,20,210,211]. These traits include (1) the efficiency with which mitochondria generate energy needed for the detoxification of non-esterified fatty acids through their incorporation into neutral lipids; an age-related decline in such efficiency accelerates age-related liponecrotic PCD by causing the excessive accumulation of monounsaturated fatty acids in cellular membranes; (2) the efficiencies with which mitochondria produce and release ROS; an age-related rise in such efficiencies above a threshold accelerates age-related liponecrotic PCD by causing oxidative damage to cellular macromolecules and organelles; and (3) the efficiency with which aged and dysfunctional mitochondria undergo an Atg32and Aup1-driven selective autophagic degradation; an age-related decline in such efficiency accelerates age-related liponecrotic PCD by impairing the maintenance of a healthy population of fully functional mitochondria [18][19][20]158,159,182,[210][211][212][213][214][215] (Figure 3). Some traits of mitochondrial functionality have not been linked to a particular lifespan checkpoint yet and may be associated with more than one of such checkpoints in chronologically aging yeast. ...
Mitochondrial functionality is vital to organismal physiology. A body of evidence supports the notion that an age-related progressive decline in mitochondrial function is a hallmark of cellular and organismal aging in evolutionarily distant eukaryotes. Studies of the baker’s yeast Saccharomyces cerevisiae, a unicellular eukaryote, have led to discoveries of genes, signaling pathways and chemical compounds that modulate longevity-defining cellular processes in eukaryotic organisms across phyla. These studies have provided deep insights into mechanistic links that exist between different traits of mitochondrial functionality and cellular aging. The molecular mechanisms underlying the essential role of mitochondria as signaling organelles in yeast aging have begun to emerge. In this review, we discuss recent progress in understanding mechanisms by which different functional states of mitochondria define yeast longevity, outline the most important unanswered questions and suggest directions for future research.
... defined by a distinct set of cellular processes that occur throughout lifespan, prior to an arrest of cell growth and division and following such arrest. 3,4,9,10,15,17,[117][118][119][120][121][122][123][124][125][126][127][128][129][130][131][132][133] These processes include cell metabolism, growth, division, organelle biogenesis, interorganellar communication, macromolecular homeostasis, stress response and death. [2][3][4]17,119,[126][127][128][129][130][131] We have proposed that all these longevity-defining cellular processes are integrated into a "biomolecular network". ...
Recent findings suggest that evolutionarily distant organisms share the key features of the aging process and exhibit similar mechanisms of its modulation by certain genetic, dietary and pharmacological interventions. The scope of this review is to analyze mechanisms that in the yeast Saccharomyces cerevisiae underlie: (1) the replicative and chronological modes of aging; (2) the convergence of these 2 modes of aging into a single aging process; (3) a programmed differentiation of aging cell communities in liquid media and on solid surfaces; and (4) longevity-defining responses of cells to some chemical compounds released to an ecosystem by other organisms populating it. Based on such analysis, we conclude that all these mechanisms are programs for upholding the long-term survival of the entire yeast population inhabiting an ecological niche; however, none of these mechanisms is a "program of aging" - i.e., a program for progressing through consecutive steps of the aging process.
